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Articles by J Xue
Total Records ( 4 ) for J Xue
  J Yang , X Liu , J Yu , L Sheng , Y Shi , Z Li , Y Hu , J Xue , L Wu , Y Liang , J Xia and D. Liang

Gene therapy has emerged as a promising approach for the lethal disorder of Duchenne muscular dystrophy (DMD). Using a novel non-viral delivery system, the human ribosomal DNA (hrDNA) targeting vector, we targeted a minidystrophin-GFP fusion gene into the hrDNA locus of HT1080 cells with a high site-specific integrated efficiency of 10–5, in which the transgene could express efficiently and continuously. The minidystrophin-GFP fusion protein was easily found to localize on the plasma membrane of HT1080 cells, indicating its possible physiologic performance. Our findings showed that the hrDNA-targeting vector might be highly useful for DMD gene therapy study.

  J Xue , P. B Thippegowda , G Hu , K Bachmaier , J. W Christman , A. B Malik and C. Tiruppathi

Activation of NF-B is essential for protease-activated receptor-1 (PAR-1)-mediated ICAM-1 expression in endothelial cells. Here we show that PAR-1 activation induces binding of both p65/RelA and NFATc1 to the NF-B binding site localized in intron-1 of the ICAM-1 gene to initiate transcription in endothelial cells. We discovered the presence of two NF-B binding sites in intron-1 (+70, NF-B site 1; +611, NF-B site 2) of the human ICAM-1 gene. Chromatin immunoprecipitation results showed that thrombin induced binding of p65/RelA and of NFATc1 specifically to intronic NF-B site 1 of the ICAM-1 gene. Electrophoretic mobility shift and supershift assays confirmed the binding of p65/RelA and NFATc1 to the intronic NF-B site 1 in thrombin-stimulated cells. Thrombin increased the expression of ICAM-1-promoter-intron 1-reporter (–1,385 to +234) construct ~25-fold and mutation of intronic NF-B site 1 markedly reduced thrombin-induced reporter expression. Moreover, inhibition of calcineurin, knockdown of either NFATc1 or p65/RelA with siRNA significantly reduced thrombin-induced ICAM-1 expression and polymorphonuclear leukocyte adhesion to endothelial cells. In contrast, NFATc1 knockdown had no effect on TNF--induced ICAM-1 expression. Thus these results suggest that p65/RelA and NFATc1 bind to the intronic NF-B site 1 sequence to induce optimal transcription of the ICAM-1 gene in response to thrombin in endothelial cells.

  J Xue , F Mraiche , D Zhou , M Karmazyn , T Oka , L Fliegel and G. G. Haddad

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

  P. B Thippegowda , V Singh , P. C Sundivakkam , J Xue , A. B Malik and C. Tiruppathi

NF-B signaling is known to induce the expression of antiapoptotic and proinflammatory genes in endothelial cells (ECs). We have shown recently that Ca2+ influx through canonical transient receptor potential (TRPC) channels activates NF-B in ECs. Here we show that Ca2+ influx signal prevents thrombin-induced apoptosis by inducing NF-B-dependent A20 expression in ECs. Knockdown of TRPC1 expressed in human umbilical vein ECs with small interfering RNA (siRNA) suppressed thrombin-induced Ca2+ influx and NF-B activation in ECs. Interestingly, we observed that thrombin induced >25% of cell death (apoptosis) in TRPC1-knockdown ECs whereas thrombin had no effect on control or control siRNA-transfected ECs. To understand the basis of EC survival, we performed gene microarray analysis using ECs. Thrombin stimulation increased only a set of NF-B-regulated genes 3- to 14-fold over basal levels in ECs. Expression of the antiapoptotic gene A20 was the highest among these upregulated genes. Like TRPC1 knockdown, thrombin induced apoptosis in A20-knockdown ECs. To address the importance of Ca2+ influx signal, we measured thrombin-induced A20 expression in control and TRPC1-knockdown ECs. Thrombin-induced p65/RelA binding to A20 promoter-specific NF-B sequence and A20 protein expression were suppressed in TRPC1-knockdown ECs compared with control ECs. Furthermore, in TRPC1-knockdown ECs, thrombin induced the expression of proapoptotic proteins caspase-3 and BAX. Importantly, thrombin-induced apoptosis in TRPC1-knockdown ECs was prevented by adenovirus-mediated expression of A20. These results suggest that Ca2+ influx via TRPC channels plays a critical role in the mechanism of cell survival signaling through A20 expression in ECs.

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